Project Summary Chronic inflammation disrupts bone metabolism and promotes bone loss. Periodontitis and peri-implantitis are the most common inflammatory bone diseases in the oral cavity. In such an inflammatory environment, bone formation and bone resorption uncouple, leading to inflammatory bone damage, tooth loss, and dental implant failure. In this study, we propose a novel mechanism by which F-BOX Protein11 (FBXO11) regulates bone development and inflammation. FBXO11 is a protein-coding gene associated with otitis media. Additionally, it functions in a broad range of biological processes including melanocyte apoptosis, cell cycle regulation, cell migration, B-cell differentiation, and epithelial cancer progression. However, the effect of FBXO11 on bone development and inflammation has not been determined. Our preliminary studies in murine osteoblasts and genomic animal model showed that FBXO11 is a critical signaling molecule governing osteogenic differentiation by inhibiting Snail1/ lysine-specific demethylase 1 (LSD1). Furthermore, we found that the FBXO11/Snail1/LSD1 signaling axis is an important mechanism underlying inflammatory bone loss in cases of chronic inflammation, such as periodontitis and peri- implantitis. The novel mechanisms identified in our proposed studies will be critical for developing molecular strategies to prevent bone loss and promote bone regeneration in periodontal and peri-implant infection. Three specific aims will address the overarching hypothesis that FBXO11 regulates osteogenic differentiation in bone development and inflammation. Specific Aim1 will determine if FBXO11 is essential for osteogenic differentiation and bone growth by using FBXO11- overexpressing and knockdown osteogenic cells cultures, bone transplant experiment, and a conditional FBXO11 knockout mouse model. Specific Aim 2 will determine if FBXO11/Snail1/LSD1 regulatory axis contributes to inflammatory bone remodeling in the polymicrobial periodontitis and peri-implantitis animals. Specific Aim 3 will determine if we can render this FBXO11 axis as novel targets to treat periodontitis and peri-implantitis that represent significant health and economic burden world widely. We propose two innovative approaches, gene therapy by genetically engineering FBXO11 transgene in osteoblasts and a local intervention with a specific LSD1 inhibitor trans-2-phenylcyclopropylamine (2-PCPA), an FDA-approved antidepressant medication to prevent bone loss and promote bone regeneration. If this proposed study validates our hypothesis of repurposing of 2-PCPA to treat inflammatory bone disease, we will consider advancing the use of 2-PCPA to treat chronic periodontitis and peri-implantitis into clinical studies.